Tacrolimus Pharmacokinetics is Associated with Gut Microbiota Diversity in Kidney Transplant Patients: Results from a Pilot Cross‐Sectional Study

Abstract

Clinical use of tacrolimus, an essential immunosuppressant following transplantation, is complexified by its high pharmacokinetic variability. The gut microbiota gains growing interest but limited investigations have evaluated its contribution to tacrolimus pharmacokinetics. Here, we explore the associations between the gut microbiota composition and tacrolimus pharmacokinetics. In this pilot cross‐sectional study (Clinicaltrial.gov NCT04360031), we recruited 93 CYP3A5 non‐expressers stabilized kidney transplant patients. Gut microbiota composition was characterized by 16S rRNA gene sequencing, tacrolimus pharmacokinetic parameters were computed, and additional demographical and medical covariates were collected. Associations between pharmacokinetic parameters or diabetic status and the gut microbiota composition, as reflected by α‐ and β‐diversity metrics, were evaluated. Patients with higher tacrolimus AUC/(dose/kg) had higher bacterial richness, and tacrolimus pharmacokinetic parameters were associated with specific bacterial taxa (e.g., Bilophila) and amplicon sequence variant (ASV) (e.g., ASV 1508 and ASV 1982 [Veillonella/unclassified Sporomusaceae]; ASV 664 [unclassified Oscillospiraceae]). Building a multiple linear regression model showed that ASV 1508 (co‐abundant with ASV 1982) and ASV 664 explained respectively 16.0% and 4.6% of the inter‐individual variability in tacrolimus AUC/(dose/kg) in CYP3A5 non‐expressers patients, when adjusting for haematocrit and age. Anaerostipes relative abundance was decreased in diabetic patients. Altogether, this pilot study revealed unprecedented links between the gut microbiota composition and diversity and tacrolimus pharmacokinetics in stable kidney transplant patients. It supports the relevance of studying the gut microbiota as an important contributor to tacrolimus pharmacokinetic variability. Elucidating the causal relationship will offer new perspectives to predict tacrolimus inter‐ and intra‐pharmacokinetic variability.

Update on the reciprocal interference between immunosuppressive therapy and gut microbiota after kidney transplantation

“…Tacrolimus pharmacokinetics is associated with gut microbiota diversity in kidney transplant patients as resulted from a pilot cross-sectional study by Degraeve et al [ 44 ].…”

Advancements in understanding the role of intestinal dysbacteriosis mediated mucosal immunity in IgA nephropathy

“…Tacrolimus, a macrolide antibiotic-type calcineurin inhibitor, has immunosuppressive effects that are 10 to 100 times stronger than CsA, both in vivo and in vitro, making it a first-line medication for anti-rejection therapy and treating recurrent IgAN post-kidney transplantation. A cross-sectional study has shown that the pharmacokinetics of tacrolimus are closely linked to the variety of the gut microbiome in patients with kidney transplants [ 143 ]. This implies that although previous research suggested genetic polymorphisms (such as gene mutations) influence the pharmacokinetics parameters of tacrolimus to some extent [ 144 ], it is now recognized that the composition and diversity of the gut microbiome are also significant factors.…”